Sepsis and septic shock in-hospital are associated with a high incidence of acute renal failure (ARF) estimated at 20 and 50%, respectively. Moreover, the combination of sepsis and ARF leads to a very high mortality ranging from 50-80%. Understanding the early vasoactive and the later proinflammatory events which cause ARF during endotoxemia would be a major medical advance, thereby allowing the development of pathogenetic-based interventions. This proposal focuses on early vasoactive endotoxemia-related events which cause systemic arterial vasodilation (e.g. nitric oxide, prostaglandins) and the compensatory vasoconstrictors (e.g. norepinephrine, angiotensin, endothelin, thromboxane) which support blood pressure but lead to renal vasoconstriction. This renal vasoconstriction renders the kidney more susceptible to the proinflammatory events of endotoxemia, such as generation of superoxide, peroxynitrite, and cytokines such as interleukin-18. In addition to selective renal denervation, there are now specific inhibitors to test the involvement of inducible nitric oxide synthase, prostaglandin and thromboxane in sepsis. Molecular biological techniques using knockout and transgemc mice will also be used to examine the role of various systemic and renal vasodilators and vasoconstrictors during endotoxemia. Understanding the role and interaction between these factors should allow the development of potential interventions in sepsis which could dramatically decrease the incidence of ARF, morbidity and mortality. The availability of potent scavengers of superoxide and antiserum to interleukin-18 also will allow not only the study of early vasoactive events but also the later pro-inflammatory events. Thus, the potential impact of the research on sepsis and sepsis-mediated ARF is substantial. The goal is to unravel the multifaceted events which occur during sepsis, including their interactions, so that effective interventions can be developed and tested in humans with sepsis. The ultimate goal therefore is to understand and prevent the ARF, morbidity and mortality associated with sepsis.